This mentored clinical research training grant seeks to provide Dr. Jonathon Chase McNeil, a pediatric infectious disease specialist, with an outstanding educational and training experience as he seeks to understand the prevalence and mechanisms of Staphylococcus aureus resistance to topical antimicrobial agents. Dr. McNeil has developed a solid training plan at Baylor College of Medicine (BCM) that will allow him to transition to a career as an independent clinician-scientist. Under the mentorship of Drs. Sheldon Kaplan, Chief of the Section of Pediatric Infectious Diseases at BCM, and Timothy Palzkill, Chair of the Department of Pharmacology, he will receive the training and experience necessary to become an excellent investigator. Topical antimicrobial resistance and S. aureus: S. aureus is a very common pathogen accounting for a wide spectrum of illness from superficial soft tissue infection to more deep seated processes. Colonization with this organism is a well described risk factor for S. aureus bacteremia as well as other forms of invasive disease. Mupirocin is a topical antibiotic used for treatment of superficial skin-and-soft-tissue infections (SSTI) due to gram-positive organisms, as well as intranasally to decrease the burden of S. aureus colonization. Numerous studies have shown a decrease in S. aureus colonization and infection when mupirocin-based decolonization is practiced in select patients, in particular cardiac surgery and ICU patients. Despite the potential for benefit, the rates of resistance can increase dramatically in closed populations or with indiscriminate use. Dr. McNeil recently investigated mupirocin resistance among previously healthy children with recurrent SSTI and found the rate of resistance to be 14.7%. Furthermore, isolates were identified which possess a high-level mupirocin resistant (HMR) phenotype but which lack the previously described resistance genes (mupA, mupB or ileS-1 mutations), suggesting an alternative mechanism of resistance. Based on these data, the overall hypothesis of this grant is that mupirocin resistance is a common occurrence among pediatric S. aureus isolates in Houston, TX and occurs through multiple mechanisms. In addition, we further hypothesize that chlorhexidine may serve as a useful alternative in cases of mupirocin resistance based on diverging mechanisms of action. Specific aim 1 will seek to determine the prevalence of mupirocin resistance in S. aureus isolates from certain high risk pediatric populations such as cardiac surgery and solid organ transplant recipients and the clinical risk factors associated with resistance. Specific aim 2 will address the issue of the mechanism of mupirocin resistance among HMR isolates lacking mupA/B and ileS-1 mutations through horizontal gene transfer, genomic analyses and cloning studies. Specific aim 3 will seek to determine the prevalence and risk factors for chlorhexidine resistance. The data collected during this course of this award will lead to an improved knowledge of the scope of the problem of mupirocin and chlorhexidine resistance, the mechanisms by which this occurs and the clinical utility of these agents. This knowledge may in turn lead to changes in medical practice. RELEVANCE: Staphylococcus aureus decolonization regimens, including mupirocin and chlorhexidine, have been shown to decrease rates of infections within surgical and ICU patients however there is the risk of developing resistance to these agents. This proposal seeks to shed light on the rates of resistance to these drugs, their mechanisms and the possible consequences to the patients involved and the hospital environment as a whole. The data generated during this work can be used to fuel changes in clinical practice and improve outcomes for these vulnerable populations.